Adenosine is known to be an endogenous modulator of a number of physiological functions and these are mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Adenosine exerts effects in cardiovascular, central nervous, respiratory systems, kidney, adipose and platelets. Recent advances in molecular biology coupled with several pharmacological studies have lead to identification of at least four subtypes of adenosine receptors, A1, A2a, A2b and A3.
In the central nervous system, A2a antagonists can have antidepressant properties and stimulate cognitive functions. There is fairly convincing prospective epidemiological evidence of a protective effect of caffeine against Parkinson's disease. Moreover, data has shown that A2a receptors density is very high in the basal ganglia, known to be important in the control of movement. Hence, selective A2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, psychoses and stroke. A2a antagonists may also be employed for the treatment or management of attention related disorders such as attention deficit disorder and attention deficit hyperactivity disorder, extra pyramidal syndrome, e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia, and disorders of abnormal movement such as restless leg syndrome and periodic limb movement in sleep. Several of these indications have been disclosed in patent applications (eg. WO 02/055083, WO 05/044245 and WO 06/132275). Adenosine A2a antagonists are also useful agents for the treatment of amyotrophic lateral sclerosis, cirrhosis, and fibrosis and fatty liver (US2007037033, WO 01/058241). A2a receptor antagonists are also useful for the mitigation of addictive behavior (WO 06/009698) and for the treatment and prevention of dermal fibrosis in diseases such as scleroderma (Arthritis & Rheumatism, 54(8), 2632-2642, 2006).
Adenosine signaling is known to serve apoptotic, angiogenic and pro-inflammatory functions and might be relevant to the pathogenesis of asthma and chronic obstructive pulmonary disease (Trends in Pharmacological Sciences, Vol. 24, No. 8, August 2003). Extracellular adenosine acts as a local modulator with a generally cytoprotective function in the body. Its effects on tissue protection and repair fall into four categories: increasing the ratio of oxygen supply to demand; protecting against ischaemic damage by cell conditioning; triggering anti-inflammatory responses; and the promotion of angiogenesis.
The A2B adenosine receptor subtype (see Feoktistov, I., Biaggioni, I. Pharmacol. Rev. 1997, 49, 381-402) has been identified in a variety of human and murine tissues and is involved in the regulation of vascular tone, smooth muscle growth, angiogenesis; hepatic glucose production, bowel movement, intestinal secretion, and mast cell degranulation. A2B receptors have been implicated in mast cell activation and asthma, control of vascular tone, cardiac myocyte contractility, cell growth and gene expression, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (Pharmacological Reviews Vol. 49, No. 4).
A2B receptors modulate mast cell function. Adenosine activates adenylate cyclase and protein kinase C, and potentiates stimulated mediator release in mouse bone marrow derived mast cells. (TiPS—April 1998 (Vol. 19)). Activation of A2B receptors in HMC-1 augments IL-8 release and potentiates PMA induced secretion of IL-8. Thus, adenosine would contribute to the asthmatic response by acting on the mast cell to enhance the release of proinflammatory mediators. (Pulmonary Pharmacology & Therapeutics 1999, 12, 111-114). In COPD, transformation of pulmonary fibroblasts into myofibroblasts is considered a major mechanism. Activation of the A2B AR is involved in this process. Selective A2B antagonists are expected to have beneficial effect on pulmonary fibrosis (Curr. Drug Targets, 2006, 7, 699-706; Am. J. Resper. Cell. Mol. Biol., 2005, 32, 228). A2B antagonists can be used as wound healing agents. Activation of the A2B AR promotes angiogenesis by increasing the release of angiogenic factors and A2B antagonists are useful to block angiogenesis (Circ. Res., 2002, 90, 531-538). A2B AR may be involved in the inhibition cardiac fibroblast (CF) proliferation (Am. J. Physiol. Heart Circ. Physiol., 2004, 287, H2478-H2486). Adenosine stimulates Cl-secretion in the intestinal epithelia pointing towards a possible treatment for cystic fibrosis patients with CFTR mutation (Am. J. Respir. Cell Mol. Biol., 2008, 39, 190-197). High affinity A2B antagonists are effective in hot plate model suggestive of the role of A2B in nociception and can be used as potential analgesic agents (The J. of Pharmacol. and Exp. Ther., 2004, 308, 358-366).
A2B receptor is involved in release of IL-6. Increasing evidence suggests that IL-6 plays a role in Alzheimer's disease in the context of inflammatory process associated with disease. Hence A2B receptor antagonist might be useful for Alzheimer's disease.
The A2B ARs are involved in the stimulation of nitric oxide production during Na+-linked glucose or glutamine absorption. They are involved in glucose production in hepatocytes upon agonist stimulation. A2B-receptor antagonists showed an anti-diabetic potential mainly by increasing plasma insulin levels under conditions when the adenosine tonus was elevated in-vivo and increased insulin release in-vitro (J Pharm. Pharmacol. 2006 December; 58(12):1639-45). Thus A2B antagonists may serve as a novel target for the treatment of this metabolic disease.
In view of the physiological effects mediated by adenosine receptor, several A2B receptor antagonists have been recently disclosed for the treatment or prevention of asthma, bronchoconstriction, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal tract disorders, cell proliferation diseases and/or diabetes mellitus. See for example WO2008002902, WO2007149277, WO2007017096, WO2007109547, WO2006091896, WO2006015357, WO2005042534, WO2005021548, WO2004106337, WO2003000694, WO2003082873, WO2003006465, WO2003053361, WO2003002566, WO2003063800, WO2003042214, WO2003035639, EP1283056, WO200073307, WO2000125210, WO2000073307, US20050119287, US20060281927.
It has now been found that compounds of the present invention are potent antagonists of the A2B adenosine receptor and can therefore be used in the treatment of the diseases mentioned herein above.
Under normal physiological conditions, A1 ARs are quiescent; however, A1 ARs are upregulated in conditions of stress, such as ischaemia, and in conditions of inflammation, typified by the inflammatory airway involvement in human asthmatics. A1 ARs are upregulated in airway epithelium and bronchial smooth muscle in human asthmatics. A1 ARs have been described on a number of different human cell types that are important in the pathophysiology of asthma, including APCs, human airway epithelial and bronchial smooth muscle cells, lymphocytes, mast cells, neutrophils, monocytes, macrophages, fibroblasts and endothelial cells. Activation of A1 ARs on these different cell types induces the release of mediators and cytokines that lead to airway hyperreactivity, inflammation and airway remodelling. Activation of A1 ARs on human asthmatic bronchial tissue produces bronchoconstriction. On human airway epithelial cells, activation of A1 ARs causes an increase in expression of the MUC 2 gene responsible for mucus hypersecretion. Moreover, activation of A1 ARs on a number of different human cells produces pro-inflammatory effects. Taken together, these effects of A1 ARs in humans suggest that the A1 AR antagonists could play potential therapeutic role in inflammatory diseases (C N Wilson, British J. of Pharm., 2008, 155, 475-86 and references cited therein). A1 AR antagonists have been shown to have efficacy in rodent models of asthma and inflammation ((J. Pharmacol. Exp. Ther. 315, 329-336, 2005; Eur. J. Pharmacol., 551, 116-124, 2006).
A1 antagonists have also been shown to have therapeutic potential in diseases such as hypertension, congestive heart failure where underlying mechanism is diuresis. There are several compounds in development for these indications (J. Am. Soc. Nephrol. 10, 714-720, 1999; Circulation, 105, 1348-1353, 2002; J. Pharmacol. Exp. Ther. 308, 846-856, 2004).
A1 AR antagonists are reported to reduce infarct size. It has been suggested that the ability of A1 AR antagonists to reduce the infarct size is also mediated by antagonism at A2B AR (Circulation, 1996, 9, 94; J. Pharmacol. Exp. Ther., 2000, 292, 3, 929-938).
Activation of A3 ARs induces the release of preformed mediators from basophils and produces bronchoconstriction, eosinophil migration into airways and mucus hypersecretion in animals, A3 AR antagonists have been recommended for development as anti-asthma drugs (Fishman and Bar-Yehuda, 2003; Nadeem and Mustafa, 2006). A3 AR antagonists have also been shown to play therapeutic role in various diseases including cardio-protection (Vasc. Pharmacol., 2005, 42, 271; J. Pharm. Exp. Ther., 2006, 319, 1200) and cancer (WO200010391).
Since several ARs have been implicated in asthma/COPD diseases pathophysiology, a pan AR antagonist may have therapeutic advantage.
It has now been found that some of the compounds of the present invention are non-selective antagonists of ARs and can therefore be used in the treatment of above mentioned diseases.